title: NOTCH1 genetic variants in patients with tricuspid calcific aortic valve stenosis.
abstract: OBJECTIVE
  Calcific aortic valve stenosis (AS) affects 2-5% of the population aged > 65 years. Functional DNA variants at the NOTCH1 locus result in bicuspid aortic valve (BAV) and severe valve calcification. The contribution of these variants to AS in the population with tricuspid aortic valve (TAV) remains to be determined.
  
  
  METHODS
  Fourteen genetic variants surrounding the NOTCH1 gene were genotyped, including rare mutations previously reported, and common polymorphisms. The study involved 457 French Canadian patients with severe tricuspid AS. Genotyping was carried out using the Illumina BeadXpress platform. Allele frequencies of common single nucleotide polymorphisms (SNPs) for patients with AS were compared to a shared control group of European ancestry (n = 3,294). In total, 88 ancestry-informative markers were used to correct for population stratification.
  
  
  RESULTS
  The mutation R1107X, previously associated with AS and BAV, was identified in a relatively young patient (aged 58 years). The mutations R1279H and V2285I were detected in 18 and 14 heterozygotes, respectively. A common polymorphism (rs13290979) located in intron 2 was significantly associated with AS (p = 0.003), which remained significant after correction for multiple testing. However, this association was no longer significant after accounting for population stratification (p = 0.088).
  
  
  CONCLUSIONS
  In this study, rare functional variants were found in the NOTCH1 gene in a French Canadian population of patients with severe tricuspid AS. This also suggests, for the first time, the presence of a common polymorphism in this gene conferring susceptibility to AS.
authors.affiliation: Centre de recherche Institut universitaire de cardiologie et de pneumologie de Québec, Laval University, Québec, Canada.
authors.forename: Valérie
authors.initials: V
authors.lastname: Ducharme
authors.forename: Sandra
authors.initials: S
authors.lastname: Guauque-Olarte
authors.forename: Nathalie
authors.initials: N
authors.lastname: Gaudreault
authors.forename: Philippe
authors.initials: P
authors.lastname: Pibarot
authors.forename: Patrick
authors.initials: P
authors.lastname: Mathieu
authors.forename: Yohan
authors.initials: Y
authors.lastname: Bossé
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001021:Aortic Valve / Q000473:pathology; D001024:Aortic Valve Stenosis / Q000235:genetics*; D002114:Calcinosis / Q000235:genetics*; D002170:Canada; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D051881:Receptor, Notch1 / Q000235:genetics*; D012720:Severity of Illness Index; D044465:White People / Q000235:genetics; D055815:Young Adult
chemical_list: C497761:NOTCH1 protein, human; D051881:Receptor, Notch1